The biological actions of estrogens and antiestrogens are manifest through two distinct high affinity receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ) (Kuiper et al, Proc. Natl. Acad. Sci. USA 93:5925 (1996), Mosselman et al, FEBS Lett. 392:49 (1996)). Estrogens are potent activators of both receptor subtypes and, with respect to ERα are known to play a critical role in the development and progression of ERα positive breast cancers. In this regard, antiestrogens, such as tamoxifen, which compete with estrogen for binding to the receptor effectively inhibit the growth of breast tumor cells (Katzenellenbogen et al, Breast Cancer Res. Treat. 44:23 (1997)). However, these cells ultimately become refractory to antiestrogen therapy, an event that is believed to stem from the ability of tamoxifen and other antiestrogens to display tissue selective agonist activity (Bertelli et al, Breast Cancer Res. Treat. 12:307 (1988), Love et al, New Engl. J. Med. 326:852 (1992), Kedar et al, Lancet 343:1318 (1994)). In particular, tamoxifen, which is an effective antagonist of ERα action in the breast, is a partial ERα agonist in the uterus, bone and cardiovascular systems (Bertelli et al, Breast Cancer Res. Treat. 12:307 (1988), Love et al, New Engl. J. Med. 326:852 (1992), Kedar et al, Lancet 343:1318 (1994)). These findings have led to the reclassification of tamoxifen and other antiestrogens as selective estrogen receptor modulators (SERMs) (Sato et al, FASEB J. 10:905 (1996)).
The molecular mechanism underlying the tissue restricted agonist activity of SERMs remains elusive. However, it is widely believed that a complex network of tissue specific co-regulatory proteins determines this specificity. Recent studies have identified a multitude of protein factors that interact with and modify the transcriptional activity of the C-terminal ligand-inducible activation function-2 (AF-2) (Robyr et al, Mol. Endocrinol. 14:329 (2000)). Relatively little is known about how the N-terminal activation function-1 (AF-1) signals. The present invention is based, at least in part, on the isolation of a novel ERα co-regulator that interacts with the ERα N-terminal domain. In particular, this protein, denoted RTA, for repressor of tamoxifen transcriptional activity, specifically inhibits tamoxifen mediated partial agonist activity. The identification of RTA makes possible methods of screening compounds for their use in the treatment of estrogen dependent diseases and disorders.